CN108267602B - Release agent for vitamin D - Google Patents
Release agent for vitamin D Download PDFInfo
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- CN108267602B CN108267602B CN201810082762.9A CN201810082762A CN108267602B CN 108267602 B CN108267602 B CN 108267602B CN 201810082762 A CN201810082762 A CN 201810082762A CN 108267602 B CN108267602 B CN 108267602B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F14/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen
- C08F14/18—Monomers containing fluorine
- C08F14/26—Tetrafluoroethene
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5002—Partitioning blood components
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
Abstract
The present invention discloses a releasing agent for vitamin D, in particular in the field of performing immunoassays for 25(OH) vitamin D in blood or blood components, in particular serum or plasma. The present invention uses a perfluoroalkyl acid or salt thereof to release 25(OH) vitamin D from vitamin D binding protein. Thereafter, the binding protein comprising 25-OH vitamin D is subjected to a competitive binding assay using a labeled vitamin D compound.
Description
The present application is a divisional application of chinese patent application No. 201180062883.3 entitled "vitamin D releasing agent" filed on 12/27/2011.
Technical Field
The present invention relates to immunoassay methods for the determination of total vitamin D or vitamin D metabolites, in particular 25-hydroxyvitamin D, in a sample of blood or blood components using reagents that release vitamin D from endogenous binding proteins, including point of care tests.
Background
The substance called "vitamin D" includes the group of fat-soluble prohormones and their metabolites and analogues. The main form of vitamin D occurring in the body is vitamin D2(ergocalciferol) and vitamin D3(cholecalciferol). The latter is an endogenous form of vitamin D, which is available to humans in the sunlightIt is formed in the skin under the influence. The former is an exogenous form of vitamin D taken by food. In the United states, vitamin D2Is used as a pharmaceutical vitamin D supplement.
Despite vitamin D2And D3Differ in the molecular structure of their side chains, but they have the same biological activity as prohormones, which are finally metabolized in two steps to 1, 25-dihydroxyvitamin D (calcitriol or 1, 25-dihydroxycholecalciferol). The previous metabolites, 25-hydroxyvitamin D or calcium diol, are obtained by transformation in the liver and are considered to be the storage forms of vitamin D in the body.
The circulating vitamin D is mainly composed of 25(OH) vitamin D3And 25(OH) vitamin D2And (4) forming. Biologically, 25(OH) vitamin D2With 25(OH) vitamin D3The same is valid. Circulating 25(OH) vitamin D2The half-life of (c) is shorter. For clinical practice, the use of the measurement of 25(OH) vitamin D is recommended3And 25(OH) vitamin D2Both were measured for 25(OH) vitamin D (1).
Vitamin D has long been recognized as an important substance, the active form of which plays a role in the formation and maintenance of bone and in other processes in the human or animal body. Thus, it increases the concentration of calcium in the bloodstream by promoting the absorption of calcium and phosphorus from food by the intestine and the reabsorption of calcium in the kidneys; thereby enabling normal mineralization of the bone and preventing hypocalcemic tetany. It is essential for bone growth and bone remodeling by osteoblasts and osteoclasts.
Vitamin D deficiency leads to impaired bone mineralization and causes osteomalacia, rickets in children and osteomalacia in adults, and possibly osteoporosis.
In recent years, vitamin D has been recognized to play many other roles in human health. It can regulate immune function and reduce inflammation. Vitamin D has also been shown to prevent colon, breast and ovarian cancer.
Therefore, it is crucial for the health of humans or animals that there is a sufficient level of vitamin D.
However, excess vitamin D (which can occur as a result of overdosing) is toxic. Some symptoms of vitamin D toxicity are hypercalcemia (elevated blood levels of calcium) resulting from increased intestinal calcium absorption. Vitamin D toxicity is known to be responsible for hypertension. Gastrointestinal symptoms of vitamin D toxicity may include anorexia, nausea and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, tension, itching (itching) and eventually renal failure.
Clearly, it is important to be able to diagnose a possible vitamin D deficiency in a subject. It is also important to be able to test possible vitamin D overages in subjects, especially subjects undergoing vitamin D supplementation. In clinical practice, serum levels of 25-hydroxy-vitamin D are considered to be a major indicator of vitamin D status. (2).
Almost all circulating 25(OH) -vitamin D in serum is bound to vitamin D binding protein (88%) and albumin (12%). Vitamin D Binding Protein (DBP) is a protein with a serum concentration of 250-400mg/L which is abundant. Vitamin D with a relatively high affinity (5 x 10) close to that of antibodies8M-1) Binding to DBP.
Accurate measurement of the concentration of vitamin D in serum requires the release of bound vitamin D from DBP.
Early methods of vitamin D measurement included an extraction step using an organic solvent (e.g., acetonitrile). Other methods rely on the dissociation of vitamin D-DBP complexes using high or low pH (WO 2004/063704). Other approaches rely on the competitive substitution of vitamin D from endogenous binding proteins using ANS (US 7,482,162). More recently, methods involving proteolytic digestion of DBP have been proposed (WO 2008/092917A 1). Armbruster discloses a method for directly measuring vitamin D by substitution of hydroxylated aromatic carboxylic acids (WO 2003/023391). The method described by Kyratsoulis relies on the release of vitamin D from vitamin D binding proteins using reagents with a pH of 3.8 to 4.8 and 5-30% DMSO, a liquid organic amide and optionally 0.5-5% short chain alcohol. Kobold provides a release method based on cationic salts with quaternary nitrogen-based ions (EP 2007/140962). US 2008/0182341 mentions stabilizers and capture ligands for use in assays for measuring analyte concentrations. These stabilizers are disclosed in the context of certain alkylamino fluorosurfactants. The inventors propose that such surfactants facilitate the measurement of free unbound analyte by stabilizing the equilibrium with respect to bound analyte. Fluorocarbon octanoic acid (fluorooctanoic acid) is mentioned as a possible hazardous substance.
Background references for vitamin D determination include Hollis BW measuring 25-hydroxyvitamin D in a clinical environment, scales and feeds Am J Clin Nutr.2008Aug; 88(2) 507S-510S; holck MF. vitamin D, extraskel health. Endocrinol Metab Clin North am.2010Jun; 39(2):381-400.
Disclosure of Invention
In one aspect, the invention provides a method for qualitative in vitro determination of the presence of 25-hydroxyvitamin D in blood or a blood component comprising:
(a) adding a perfluoroalkanoic acid having a carbon chain length of 4 to 12 carbon atoms or a salt thereof to the sample to enable release of vitamin D from the vitamin D binding protein;
(b) optionally diluting the sample with a diluent;
(c) incubating the mixture with the immobilized binding protein, in particular an anti-vitamin D antibody;
(d) contacting the sample with a conjugate of vitamin D and a functional label that binds to the anti-vitamin D antibody in a competitive manner;
(e) determining the concentration of labeled vitamin D compound bound to the binding protein.
In another aspect, the invention resides in a kit for carrying out the above method.
In yet another aspect, the method may be used for "point of care" testing. The latter refers to testing at or near the patient care location, i.e. instead of taking blood samples and sending them to a diagnostic laboratory, the samples can be immediately introduced into a portable, preferably hand-held device capable of performing the assay in as limited a number of steps as possible and as limited a number of manual operations as possible.
Drawings
FIG. 1 shows a calibration curve for 25(OH) vitamin D.
Figure 2 provides a graph of the results obtained by comparison of the release with perfluorohexanoic acid (PFHxA) and with perfluorooctanoic acid (PFOA).
Detailed Description
In a broad sense, the present invention relates to the determination of vitamin D in blood or blood components, in particular serum or plasma, by immunoassay using a perfluoroalkyi acid or salt thereof with a carbon chain length of 4 to 12 to release vitamin D from endogenous binding proteins.
Conceivably, a perfluoroalkylcarboxylic acid or perfluorosulfonic acid or a salt thereof may be used in the present invention. Specifically, perfluorohexanoic acid (PFHxA) or perfluorooctanoic acid (PFOA) may be used.
The assay generally comprises:
(a) adding a diluent/assay buffer to the sample;
(b) adding magnetic particles coated with anti-vitamin D antibody;
(c) incubating the sample for a time;
(d) adding a combination of vitamin D and a functional marker;
(e) determining the amount of conjugate of vitamin D and the functional label bound to the antibody.
These samples may be drawn from a subject, particularly a human, who wishes to determine the presence of 25-OH vitamin D in blood in any manner known in the art.
Preferably, the sample is diluted with an aqueous diluent. Preferably, the diluent is an assay buffer. Dilution can be performed before, during or after antibody addition. The sample diluent or assay diluent may be water-based and will preferably be a buffer solution. Preferably, the buffered pH is from 6.0 to 8.0. Suitable diluents include, for example, phosphate citrate buffer. The concentration of the perfluoroalkyl acid in the buffer should be 0.1% to 3%, preferably 0.5%. Suitable buffer solutions are conventional in the art and need not be described herein.
The perfluoroalkyl acid may be added in a separate manner, but preferably the perfluoroalkyl acid is contained in the sample diluent, preferably in the assay buffer.
The sample is contacted with an anti-25 (OH) vitamin D antibody. The latter may be added to the sample or the sample may be transferred to a reaction vial containing the binding protein.
Antibodies to vitamin D are known in the art and are widely used in existing vitamin D immunoassays. These same antibodies, as well as other binding proteins, can also be used in the present invention. For example, instead of vitamin D antibodies, antibody fragments as produced by phage display technology may be used. Suitable antibodies may be monoclonal or polyclonal antibodies. They may be obtained in known manner, e.g. polyclonal goat anti-vitamin D, polyclonal rabbit anti-vitamin D or any other suitable vitamin D antibody known in the art from vitamin D immunoassay applications. Suitable antibodies are obtained from the following references, for example: hollis, clin. chem 31/11,1815-1819 (1985); hollis, clin. chem 39/3,529-533 (1993).
Preferably, the antibody used is immobilized. Preferably, they are used in the form of particles comprising a solid carrier. Typically, the antibody is coated on a solid phase, e.g., on a microtiter plate. In a preferred embodiment, the antibodies are coated on magnetic particles, which facilitates their separation in a magnetic field.
After addition of the antibody, the sample was incubated. The time required will depend on the circumstances such as reagent concentration, type of binding protein and conditions during incubation, e.g., shaking and temperature. Typically, the incubation time will be in the range of 10 seconds to several hours, preferably 1 minute to 1 hour. For automated platforms, short incubation times (10 seconds to 10 minutes, preferably 30 seconds to 30 minutes) are preferred.
After the first incubation period, a conjugate of vitamin D and a functional marker is added. A variety of labeled compounds are known that can be used as competitive binding antigens in immunoassays for vitamin D measurement. Typical labels are radioactive labels, fluorescent labels, luminescent labels, biotin labels, gold labels, enzyme labels. Competitive binding assays are known to the skilled person and do not need to be described, in particular because this part of the method of the invention can be performed using any label known to be suitable for vitamin D measurement. In particular, markers that can be used are those disclosed in the above references of existing vitamin D immunoassays.
The concentration can be measured by the marker and thus the concentration of vitamin D in the sample is determined. It will be understood that the meaning (interpretation) of the measured values is determined by calibration measurements, i.e. by the response of the calibrator in the same assay.
Calibration of the assay of the invention may be performed by providing a calibrator comprising a predetermined concentration of 25-OH vitamin D. Preferably, the concentration of vitamin D in the calibrator is determined using the LC-MS method.
In another aspect, the invention provides a product in the form of an immunoassay for the determination of 25-OH vitamin D in blood or a blood component, wherein the assay utilizes a method according to any one of the above embodiments. More specifically, such products will be provided in the form of kits for performing immunoassays. The kit may comprise the release reagent concerned (i.e. the antibody), the labelled vitamin D compound and a diluent/assay buffer. These reagents may be provided separately and therefore form a kit only when they are used in the assay of the invention. Preferably, the reagents are provided together as part of a kit, preferably packaged together. Optionally, the kit comprises a container for a blood or blood component sample, but this may also be provided separately as is customary. Typically, the kit comprises a binding agent immobilized on a solid phase and separately bound vitamin D. As is customary in the art, the other kit components will depend on the label chosen, since different labels may require different reagents.
It is to be understood that the invention is not limited to the embodiments and formulations described above. It is also to be understood that the term "comprising" does not exclude other elements or steps. Where an indefinite or definite article is used, when referring to a singular noun e.g. "a", "an", "the", this includes a plural of that noun unless something else is specifically stated.
The invention will now be illustrated with reference to the following non-limiting examples and non-limiting drawings.
Examples
Measurement of vitamin D
Assays were performed using an automated platform. To 15. mu.l of sample was added 255. mu.l of sample diluent/assay buffer. A100. mu.l aliquot of the diluted sample was transferred to a second incubation well. A volume of 50. mu.l of magnetic particles coated with monoclonal antibody was added to the diluted sample and incubated at 37 ℃ for 45 minutes. Subsequently, 50. mu.l of biotinylated vitamin D solution was added and incubated at 37 ℃ for 7 minutes. Then, 50. mu.l of streptavidin-acridinium ester (acridinium ester) solution was added and incubated at 37 ℃ for another 7 minutes. After magnetic separation of bound and free biotinylated vitamin D, the bound acridinium ester was quantified.
Material
Paramagnetic particles: magnetic particles (Invitrogen, M280 tosyl activated, 2.8 μ M) were coated with polyclonal antibody against mouse IgG (5 μ g/mg magnetic particles). The particles were coated on a roller (roller) during 16 hours at a concentration of 0.5mg/ml in 0.01M PBS, 0.138M NaCl (pH 7.4). Finally, the particles were blocked (block) with 0.05M Tris/0.05% BSA containing 0.1% Proclin-950. The granules were coated with a second layer of anti-vitamin D monoclonal antibody at a concentration of 0.4. mu.g/mg of granules at 37 ℃ over a period of 16 hours.
Sample diluent:consists of 0.1M TRIS buffer (pH 8.0) containing 0.05% BSA and 0.5% PFOA.
Conjugate:(i.e., labeled vitamin D compound) is biotinylated vitamin D. The conjugate was present at a concentration of 0.5ng/ml in 0.1M Tris buffer (pH 8.0) containing 0.05% bovine serum albumin.
Scheme(s)
To 15. mu.l of sample was added 255. mu.l of sample diluent/assay buffer. A100. mu.l aliquot of the diluted sample was transferred to a second incubation well. A volume of 50. mu.l of monoclonal antibody-coated magnetic particles was added to the diluted sample and incubated at 37 ℃ for 45 minutes. Subsequently, 50. mu.l of biotinylated vitamin D solution was added and incubated at 37 ℃ for 7 minutes. Then, 50. mu.l of streptavidin-acridinium ester solution was added and incubated at 37 ℃ for a further 7 minutes. After magnetic separation of bound and free biotinylated vitamin D, the bound acridinium ester was quantified. The chemiluminescent signal is generated by the addition of a trigger. The signal produced in the cuvette is inversely proportional to the concentration of 25(OH) vitamin D in the sample or calibrator. The concentration of 25(OH) vitamin D in the original sample can be calculated by comparing the unknown signal to the calibrator response.
Results
In the following table and in fig. 1, calibration curves are shown. Preparation of 25(OH) vitamin D in vitamin D-free serum3A calibrator in the range of 0-136 ng/ml.
Biotinylated 25(OH) vitamin D was replaced to a level of 7% (136 ng/ml).
The sample sets were measured using perfluorooctanoic acid release and perfluorohexanoic acid release. The results correlate well (r ═ 0.990), indicating that both compounds can be used (figure 2).
Watch (A)
Table 1.25(OH) vitamin D calibration curve.
Claims (8)
1. An immunoassay method for the determination of 25-hydroxyvitamin D in a sample of blood or blood components using a reagent that releases vitamin D from endogenous binding proteins, wherein the reagent is a perfluoroalkanoic acid or salt thereof having a carbon chain length of 4-12, contained in an assay buffer at a concentration of 0.5-3%, the method comprising determining the total concentration of 25-hydroxyvitamin D with reference to a calibrator concentration for total 25-OH vitamin D.
2. The method of claim 1, wherein the perfluoroalkyl acid is selected from the group consisting of perfluorohexanoic acid, perfluorooctanoic acid, and mixtures thereof.
3. The method according to claim 1 or 2, which is a method for qualitative determination of the presence of 25-hydroxyvitamin D in blood or blood components in vitro comprising:
(a) adding the assay buffer to the sample;
(b) incubating the mixture of the assay buffer and the sample with an anti-vitamin D antibody;
(c) contacting the sample with a conjugate of vitamin D and a functional label that binds to the anti-vitamin D antibody in a competitive manner, the functional label being selected from the group consisting of a radioactive label, a fluorescent label, a luminescent label, a biotin label, a gold label, and an enzymatic label;
(d) determining the concentration of labeled vitamin D compound bound to the anti-vitamin D antibody with reference to the calibrator concentration for total 25-OH vitamin D.
4. The method of claim 3, wherein the sample is human serum or plasma.
5. The method of claim 3, wherein the anti-vitamin D antibody is provided in a form coated on magnetic particles.
6. The method of claim 2, wherein the perfluorooctanoic acid or derivative thereof is selected from the group consisting of perfluorooctanoic acid, ammonium perfluorooctanoate, and perfluorooctane sulfonate.
7. A kit for performing an immunoassay using the method according to any one of claims 3 to 6, the kit comprising an antibody specific for 25-OH vitamin D immobilized on a solid phase, a conjugate of vitamin D and a functional label selected from the group consisting of a radioactive label, a fluorescent label, a luminescent label, a biotin label, a gold label and an enzyme label, and an assay buffer comprising 0.5 to 3% of a perfluoroalkyl acid or a salt thereof having a carbon chain length of 4 to 12.
8. Use of a perfluoroalkyl acid or salt thereof having a carbon chain length of 4-12 to release vitamin D from an endogenous binding protein in an immunoassay for the purpose of determining the total vitamin D concentration in a sample.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10197208 | 2010-12-28 | ||
| EP10197208.1 | 2010-12-28 | ||
| EP11169314 | 2011-06-09 | ||
| EP11169314.9 | 2011-06-09 | ||
| CN2011800628833A CN103282390A (en) | 2010-12-28 | 2011-12-27 | Release reagent for vitamin d |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800628833A Division CN103282390A (en) | 2010-12-28 | 2011-12-27 | Release reagent for vitamin d |
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| Publication Number | Publication Date |
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| CN108267602A CN108267602A (en) | 2018-07-10 |
| CN108267602B true CN108267602B (en) | 2020-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201810082762.9A Active CN108267602B (en) | 2010-12-28 | 2011-12-27 | Release agent for vitamin D |
| CN2011800628833A Pending CN103282390A (en) | 2010-12-28 | 2011-12-27 | Release reagent for vitamin d |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2011800628833A Pending CN103282390A (en) | 2010-12-28 | 2011-12-27 | Release reagent for vitamin d |
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| US (1) | US10422805B2 (en) |
| EP (1) | EP2635611B1 (en) |
| JP (2) | JP6138053B2 (en) |
| KR (1) | KR101838328B1 (en) |
| CN (2) | CN108267602B (en) |
| AU (1) | AU2011353202B2 (en) |
| CA (1) | CA2821415C (en) |
| CL (1) | CL2013001883A1 (en) |
| ES (1) | ES2614817T3 (en) |
| RU (1) | RU2579312C2 (en) |
| WO (1) | WO2012091569A1 (en) |
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| AU2014322925B2 (en) * | 2013-09-17 | 2020-07-02 | Biomerieux | Solution for dissociating vitamin D from vitamin D-binding protein, associated detection method and use |
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| EP3387447A4 (en) | 2015-12-11 | 2019-08-28 | Opko Diagnostics, LLC | Fluidic systems involving incubation samples and/or reagents |
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| JP6218916B1 (en) * | 2016-12-28 | 2017-10-25 | Jsr株式会社 | Magnetic particle dispersion |
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| CN115850141A (en) * | 2019-02-01 | 2023-03-28 | 科美博阳诊断技术(上海)有限公司 | Intermediate compound and preparation method and application thereof |
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2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981779A (en) * | 1995-12-29 | 1999-11-09 | A And D Assay, Incorporated | Labeled vitamin D compounds and the use thereof |
| WO2003023391A2 (en) * | 2001-09-12 | 2003-03-20 | Immundiagnostik Ag | Method and agents for direct measurement of vitamin d compounds in serum or plasma |
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| RU2013127156A (en) | 2015-02-10 |
| KR20140019780A (en) | 2014-02-17 |
| JP6560271B2 (en) | 2019-08-14 |
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| RU2579312C2 (en) | 2016-04-10 |
| ES2614817T3 (en) | 2017-06-02 |
| US10422805B2 (en) | 2019-09-24 |
| CN108267602A (en) | 2018-07-10 |
| JP2014501392A (en) | 2014-01-20 |
| US20140147935A1 (en) | 2014-05-29 |
| JP2017083475A (en) | 2017-05-18 |
| WO2012091569A1 (en) | 2012-07-05 |
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| CA2821415A1 (en) | 2012-07-05 |
| EP2635611A1 (en) | 2013-09-11 |
| CN103282390A (en) | 2013-09-04 |
| CA2821415C (en) | 2017-08-01 |
| KR101838328B1 (en) | 2018-03-13 |
| AU2011353202A1 (en) | 2013-07-11 |
| JP6138053B2 (en) | 2017-05-31 |
| AU2011353202B2 (en) | 2015-07-09 |
| EP2635611B1 (en) | 2017-01-11 |
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